Nicastrin binds to membrane-tethered Notch

Chen, Fusheng; Yu, Gang; Arawaka, Shigeki; Nakagawa, Masaki; Kawarai, Toshitaka; Yu, Hao; Tandon, Anurag; Supala, Agnes; Song, Yong-Ak; Rogaeva, Ekaterina; Milman, Paul; Sato, Christine; Yu, Cong; Janus, Christopher; Lee, Julie; Song, Lixin; Zhang, Lili; Fraser, Paul E.; George-Hyslop, Peter St

doi:10.1038/35087069

Cited by 120 publications

(120 citation statements)

References 31 publications

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“…Therefore, Notch and APP have distinct ␥-secretase pathways. Our conclusion is consistent with earlier studies that showed that APP and Notch do not compete for ␥-secretase activity in the cell (44,45). A lack of competition between the two substrates could arise because the processing of Notch and APP occurs in different subcellular compartments, or because the concentration of both substrates is not saturated.…”

Section: Discussionsupporting

confidence: 82%

Processing of Notch and amyloid precursor protein by γ-secretase is spatially distinct

Tarassishin

Yin

Bassit

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

103

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␥-Secretase activity is associated with a presenilin (PS)-containing macromolecular complex. Whether PS contains the active site of ␥-secretase has been controversial. One challenge is to find PS that is engaged in the active ␥-secretase complex at the cell surface, where some substrates appear to be processed. In this study, we developed an intact cell photolabeling technique that allows the direct visualization of active ␥-secretase at the cell surface. We demonstrated that active ␥-secretase is present in the plasma membrane. Moreover, the PS1 heterodimer is specifically photolabeled at the cell surface by a potent inhibitor that binds to only the active ␥-secretase. We also explored the cellular processing sites of ␥-secretase for amyloid precursor protein (APP) and Notch by using small molecular probes. MRL631, a ␥-secretase inhibitor that is unable to penetrate the cell membrane, significantly blocks ␥-secretase-mediated Notch cleavage but has little effect on APP processing. These results indicate that Notch is processed at the cell surface and that the majority of APP is processed by intracellular ␥-secretase. Furthermore, the fact that inhibitors first target ␥-secretase in the plasma membrane for Notch processing, and not for APP, will have important implications for drug development to treat Alzheimer's disease and cancer.intact cell photolabeling ͉ intramembrane protease ͉ presenilin

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Section: Discussionsupporting

confidence: 82%

Processing of Notch and amyloid precursor protein by γ-secretase is spatially distinct

Tarassishin

Yin

Bassit

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

103

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“…Deletions within the ectodomain of NCT have been shown to block interactions with PS1 as judged by coimmunoprecipitation and to reduce or ablate ␥-secretase activity (17,31,41,42). It is not possible to conclude if these results are due to the genetic deletion of residues or regions in NCT that are needed for specific interactions with one or more ␥-secretase components, or if they are due to gross misfolding of the modified NCT constructs.…”

Section: Discussionmentioning

confidence: 82%

“…Thus, we sought a homolog of hNCT that would fulfill this requirement and found one in the form of ceNCT. Genetic evidence indicates that ceNCT has functions that are broadly similar to those of its human counterpart, particularly with regards to ␥-secretase-mediated cleavage of Notch (11,17,26,42). In addition, while sharing only 21% amino acid identity, the large majority of Cys residues are conserved between the two molecules, suggesting a conserved overall structure.…”

Section: Discussionmentioning

confidence: 91%

The Transmembrane Domain Region of Nicastrin Mediates Direct Interactions with APH-1 and the γ-Secretase Complex

Morais

Crystal

Pijak

et al. 2003

Journal of Biological Chemistry

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Nicastrin (NCT) is a type I integral membrane protein that is one of the four essential components of the ␥-secretase complex, a protein assembly that catalyzes the intramembranous cleavage of the amyloid precursor protein and Notch. Other ␥-secretase components include presenilin-1 (PS1), APH-1, and PEN-2, all of which span the membrane multiple times. The mechanism by which NCT associates with the ␥-secretase complex and regulates its activity is unclear. To avoid the misfolding phenotype often associated with introducing deletions or mutations into heavily glycosylated and disulfidebonded proteins such as NCT, we produced chimeras between human (hNCT) and Caenorhabditis elegans NCT (ceNCT). Although ceNCT did not associate with human ␥-secretase components, all of the ceNCT/hNCT chimeras interacted with ␥-secretase components from human, C. elegans, or both, indicating that they folded correctly. A region at the C-terminal end of hNCT, encompassing the last 50 residues of its ectodomain, the transmembrane domain, and the cytoplasmic domain was important for mediating interactions with human PS1, APH-1, and PEN-2. This finding is consistent with the fact that the bulk of the ␥-secretase complex proteins resides within the membrane, with relatively small extramembranous domains. Finally, hNCT associated with hAPH-1 in the absence of PS, consistent with NCT and APH-1 forming a subcomplex prior to association with PS1 and PEN-2 and indicating that the interactions between NCT with PS1 may be indirect or stabilized by the presence of APH-1.

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“…Nicastrin, an integral component of the γ-secretase complex, is a transmembrane glycoprotein with a long hydrophilic N-terminal domain containing multiple glycosylation sites, a hydrophobic transmembrane domain and a short hydrophilic C-terminal tail [6,55]. Nicastrin was first identified in a C. elegans genetic screen as aph-2, an essential component of GLP-1/ Notch signaling pathway in early embryos [16].…”

Section: Introductionmentioning

confidence: 99%

Cellular distribution of γ-secretase subunit nicastrin in the developing and adult rat brains

Kodam

Vetrivel

Wang

et al. 2008

Neurobiology of Aging

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Nicastrin and presenilin 1 are integral components of the high molecular weight γ-secretase complexes that regulate proteolytic processing of various type I membrane proteins including amyloid precursor protein and Notch. At present, there is little information regarding the cellular distribution of nicastrin in the developing or adult rat brain. We report here, using immunoblotting and immunohistochemical methods, that nicastrin in the adult rat brain is widely expressed and colocalized with presenilin 1 in select neuronal populations within all major areas, including the basal forebrain, striatum, cortex, hippocampus, amygdala, thalamus, hypothalamus, cerebellum and brainstem. We also observed dense neuropil labeling in many regions in the brain, suggesting that nicastrin gets transported to dendrites and/or axon terminals in the central nervous system. The levels of nicastrin are found to be relatively high at the early stages of postnatal development and then declined gradually to reach the adult profile. At the cellular level, nicastrin is localized predominantly in neuronal cell bodies at early postanatal stages, but is apparent both in cell bodies and dendrites/ neuropil in all brain regions at the later stages. The regulation of nicastrin expression and localization during development and its distribution in a wide spectrum of neurons in the postnatal and adult rat brains provide an anatomical basis to suggest a multifunctional role for the γ-secretase complex in the developing and adult rat brains.

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Nicastrin binds to membrane-tethered Notch

Cited by 120 publications

References 31 publications

Processing of Notch and amyloid precursor protein by γ-secretase is spatially distinct

Processing of Notch and amyloid precursor protein by γ-secretase is spatially distinct

The Transmembrane Domain Region of Nicastrin Mediates Direct Interactions with APH-1 and the γ-Secretase Complex

Cellular distribution of γ-secretase subunit nicastrin in the developing and adult rat brains

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